This invention relates to novel pyrimidinone derivatives and the pharmaceutically acceptable salts thereof. This invention also relates to process for preparing of the novel pyrimidinone derivatives and pharmaceutical composition containing the pyrimidinone derivatives.
The compounds of this invention and the pharmaceutically acceptable salts thereof are useful as angiotensin II antagonists especially, in treatment of various cardiovascular diseases caused by angiotensin II.
Renin-angiotensin system plays a central role in the regulation of blood pressure in human body. Angiotensin II, consisting of eight amino acids, is produced during the cleavage of angiotensin I by angiotensin converting enzyme(ACE) localized on the arterial blood vessels of lung, etc., and then involved in hypertension development. Angiotensin II, the final product of Renin-angiotensin system, exerts its action to elevate blood pressure and increase electrolyte concentration by interacting with specific receptors present in blood vessel, smooth muscle, kidney or adrenal gland. Thus, as a way of controlling hypertension several antagonistic compounds have been explored to inhibit the effect of angiotensin II by blocking its receptors.
Peptide antagonists analogous to angiotensin II are known, but their clinical applications have been limited because of their short half-life, extensive inactivation after oral administration and above all the partial agonistic activity.
Recently, several non-peptide compounds have been reported as angiotensin II antagonists. European Patent Application Laying-Open Publication Nos. 028,834 and 253310 disclose Imidazole derivatives substituted by biphenyl (for example, Losartan) and European Patent Application Laying-Open Publication No. 245,637, imidazopyridine derivatives (for example, L158,809) as potent angiotensin II antagonists.
In European Patent Application Laying-Open Publication Nos. 407,342, 419,048 and 445,811, pyrimidinone compounds similar to the compounds of this invention in their 6 membered heterocyclic ring structure are disclosed inclusively as a general formula without illustrative enough to support it. Further, the compounds described therein show relatively low activities(10.sup.-6 mol for 60.about.70% inhibition in in vitro blood vessel dilation study) than imidazole derivatives known in the above mentioned application.